Renal sodium reabsorption is a major determinant of intravascular volume in humans and consequently contributes directly to blood pressure determination. Because of the enormous amount of sodium filtered and reabsorbed by the kidney, a very small variation in net sodium reabsorption could have substantial effects on blood pressure. These considerations raise the possibility that inherited variation in one or more of the renal sodium transport systems could contribute to the pathogenesis of hypertension in humans. The recent cloning of the key mediators of renal sodium reabsorption in different nephron segments by participants in our SCOR now provides a unique opportunity to critically test this hypothesis. The first test has provided dramatic proof of the principle: participants in our SCOR have demonstrated that-Liddle's syndrome, an autosomal dominant form of human hypertension, is caused by mutation in the beta subunit of the mineralocorticoid-regulated epithelial sodium channel. Functional assays of mutant channels performed by SCOR participants documents constitutive overactivity of these channels, and indicate the presence of a previously unknown mechanism by which this channel is normally regulated. These findings provide a paradigm for the genetic studies to be pursued in this SCOR. Taking advantage of the great strength in ion transport physiology among SCOR participants we will perform original studies on the molecular physiology of newly cloned ion transporters in order to gain new insight into the function and regulation of these transport systems and will use genetic approaches to search for mutations in these systems. The functional consequences of identified mutations will be assessed by analysis of function in cell-based expression systems. Human populations to be studied include families with Liddle's syndrome, Gordon's syndrome and pseudohypoaldosteronism type I- all inherited single gene defects in sodium homeostasis- as well as Caucasian hypertensive subjects and African American hypertensive sibling pairs. In parallel with these genetic studies, additional biochemical, molecular and physiologic studies of these transporters and other novel ion transport systems will be pursued These studies will provide a comprehensive analysis of renal sodium transport systems and will permit conclusive assessment of their role in the pathogenesis of human hypertension. In addition, we will use general linkage approaches to screen for inherited predisposition to end-stage renal disease in African Americans, a study which may provide new clues into the causes of this too-common end-point of hypertension.